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Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens a Randomized Clinical Trial

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Fenfluramine for Treatment-Resistant Seizures in Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens a Randomized Clinical Trial Research JAMA Neurology | Original Investigation Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial Rima Nabbout, MD, PhD; Arun Mistry, MBChB, MRCP(UK), MRCPCH; Sameer Zuberi, MD; Nathalie Villeneuve, MD; Antonio Gil-Nagel, MD; Rocio Sanchez-Carpintero, MD; Ulrich Stephani, MD; Linda Laux, MD; Elaine Wirrell, MD; Kelly Knupp, MD; Catherine Chiron, MD, PhD; Gail Farfel, PhD; Bradley S. Galer, MD; Glenn Morrison, PhD; Michael Lock, PhD; Anupam Agarwal, MD; Stéphane Auvin, MD, PhD; for the FAiRE, DS Study Group Supplemental content IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (Ն50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Author Affiliations: Author TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02926898 affiliations are listed at the end of this article. Group Information: The FAiRE, DS Study Group members appear at the end of the article. Corresponding Author: Bradley S. Galer, MD, Zogenix, 5959 Horton St, JAMA Neurol. doi:10.1001/jamaneurol.2019.4113 Ste 500, Emeryville, CA 94608 Published online December 2, 2019. ([email protected]). (Reprinted) E1 Downloaded From: https://jamanetwork.com/ on 12/02/2019 Research Original Investigation Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol ravet syndrome (DS) is a severe developmental epi- leptic encephalopathy with an incidence of 1:15 700 to Key Points 1:40 900.1 Dravet syndrome typically presents in the D Question Is fenfluramine safe and effective for treating patients first year of life with frequent, pharmacoresistant convulsive with Dravet syndrome who have frequent seizures despite taking seizures,1,2 which may contribute to intellectual disability and a stiripentol-inclusive antiepileptic drug regimen? impairments in motor control, behavior, and cognition.3 Most Findings Oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) patients (70%-85%) have sodium voltage-gated channel al- provided a 54.0% greater reduction in mean monthly convulsive pha subunit 1 gene (SCN1A) sodium channel alterations, al- seizure frequency than placebo in patients with Dravet syndrome though diagnosis is solely based on electroclinical criteria.1,2,4 who were taking stiripentol-containing antiepileptic drug Patients with DS who are younger than 18 years have in- regimens; a significantly greater proportion of patients who were creased risk of sudden unexpected death in epilepsy, with a taking fenfluramine (vs placebo) experienced a clinically Ն Ն mortality rate of 7% to 18%. Frequency of generalized tonic- meaningful ( 50%) or profound ( 75%) reduction in monthly convulsive seizure frequency. The most common adverse events clonic seizures is a major risk factor for this outcome.5-7 included decreased appetite, pyrexia, fatigue, and diarrhea; no Even with polypharmacy, seizures remain poorly con- patient developed valvular heart disease or pulmonary trolled in most patients with DS. In a survey of 274 patients, hypertension. 45% receiving multitreatment modalities continued to expe- Meaning Adjunctive fenfluramine may be a safe, effective new rience more than 4 tonic-clonic seizures per month.8 Until the treatment option for patients with Dravet syndrome with seizures recent approval of cannabidiol and stiripentol by the US Food that are not controlled by a regimen including stiripentol. and Drug Administration, stiripentol in combination with val- proate and clobazam remained the only approved treatment for DS outside of the United States. Despite treatment with stiripentol-inclusive antiepileptic drug (AED) regimens, 38% The study complied with current International Council for of patients were reported to present with weekly seizures Harmonisation Good Clinical Practice guidelines, as de- (>3 per month).8,9 Given the risks of sudden unexpected death scribed in International Council for Harmonisation Topic E6 in epilepsy, cognitive deficits, and other neurological conse- Guidelines.14 The protocol was approved by applicable regu- quences putatively caused at least in part by poorly con- latory authorities and an independent ethics committee or in- trolled seizures, there remains an urgent unmet need for treat- stitutional review board at each participating institution. All ing DS.9-11 patients or their legal representatives provided written in- Results from a recent phase 3, placebo-controlled random- formed consent before enrollment. ized clinical study (Study 1 [NCT02682927; NCT02826863])12 demonstrated that fenfluramine provided a significantly Patients and Eligibility Criteria greater reduction in monthly convulsive seizure frequency Patients were male or female; aged 2 to 18 years (inclusive); (MCSF) vs placebo. Patients receiving stiripentol were ex- receiving a stable, stiripentol-inclusive AED regimen; and free cluded from Study 1 because pharmacokinetic data were not of cardiovascular disease on an echocardiogram, electrocar- yet available to evaluate dosage modifications needed to com- diogram, or physical examination. The diagnosis of DS was vali- pensate for an expected fenfluramine-stiripentol drug inter- dated by a central committee, the Epilepsy Study Consor- action. Given the widespread use of stiripentol for DS, it is im- tium (eTable 1 in Supplement 1). Key exclusion criteria were portant to assess the benefit and tolerability of add-on pulmonary arterial hypertension (PAH) or a current condi- fenfluramine in stiripentol-containing AED regimens. A phase tion or history of cardiovascular or cerebrovascular disease 1 pharmacokinetic study and earlier physiologically based phar- (eg, cardiac valvulopathy, myocardial infarction, stroke) and macokinetic modeling were used to select a fenfluramine dose concomitant treatment with modulators of serotonergic ac- of 0.4 mg/kg/d (maximum, 17 mg/d) added to stiripentol- tivity, AEDs with sodium channel antagonist activity, or can- valproate-clobazam triple therapy.13 Here, we evaluate effi- nabinoid products. cacy and safety of add-on fenfluramine in patients with DS re- ceiving stiripentol-inclusive AED regimens. Trial Procedures This study evaluated the safety and efficacy of twice-daily fen- fluramine (administered as a fenfluramine hydrochloride oral Methods solution containing 2.2 mg/mL of fenfluramine) added to a stiripentol-inclusive AED regimen (plus valproate or cloba- Trial Design, Ethics, and Oversight zam, at a minimum) in children and young adults with DS In this double-blind, parallel-group, placebo-controlled, phase (eFigure 1 in Supplement 1). In a drug-interaction study (Co- 3 randomized clinical study, patients with DS with seizures that hort 1 [NCT02926898]), fenfluramine was administered with were poorly controlled with current AED regimens, which had clobazam and valproate and with and without
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